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NOTCH3 variants and risk of ischemic stroke.
[cadasil]
Mutations
within
the
NOTCH
3
gene
cause
cerebral
autosomal
dominant
arteriopathy
with
subcortical
infarcts
and
leukoencephalopathy
(
CADASIL
)
.
CADASIL
mutations
appear
to
be
restricted
to
the
first
twenty-
four
exons
,
resulting
in
the
gain
or
loss
of
a
cysteine
amino
acid
.
The
role
of
other
exonic
NOTCH
3
variation
not
involving
cysteine
residues
and
mutations
in
exons
25
-
33
in
ischemic
stroke
remains
unresolved
.
All
33
exons
of
NOTCH
3
were
sequenced
in
269
Caucasian
probands
from
the
Siblings
With
Ischemic
Stroke
Study
(
SWISS
)
,
a
70
-
center
North
American
affected
sibling
pair
study
and
95
healthy
Caucasian
control
subjects
.
Variants
identified
by
sequencing
in
the
SWISS
probands
were
then
tested
for
association
with
ischemic
stroke
using
US
Caucasian
controls
collected
at
the
Mayo
Clinic
(
n
=
654
)
,
and
further
assessed
in
a
Caucasian
(
n
=
802
)
and
African
American
(
n
=
298
)
patient-control
series
collected
through
the
Ischemic
Stroke
Genetics
Study
(
ISGS
)
.
Sequencing
of
the
269
SWISS
probands
identified
one
(
0
.
4
%
)
with
small
vessel
type
stroke
carrying
a
known
CADASIL
mutation
(
p
.
R
558
C
;
Exon
11
)
.
Of
the
19
common
NOTCH
3
variants
identified
,
the
only
variant
significantly
associated
with
ischemic
stroke
after
multiple
testing
adjustment
was
p
.
R
1560
P
(
rs
78501403
;
Exon
25
)
in
the
combined
SWISS
and
ISGS
Caucasian
series
(
Odds
Ratio
[
OR
]
0
.
50
,
P
=
0
.
0022
)
where
presence
of
the
minor
allele
was
protective
against
ischemic
stroke
.
Although
only
significant
prior
to
adjustment
for
multiple
testing
,
p
.
T
101
T
(
rs
3815188
;
Exon
3
)
was
associated
with
an
increased
risk
of
small
-vessel
stroke
(
OR
:
1
.
56
,
P
=
0
.
008
)
and
p
.
P
380
P
(
rs
61749020
;
Exon
7
)
was
associated
with
decreased
risk
of
large
-vessel
stroke
(
OR
:
0
.
35
,
P
=
0
.
047
)
in
Caucasians
.
No
significant
associations
were
observed
in
the
small
African
American
series
.
Cysteine-affecting
NOTCH
3
mutations
are
rare
in
patients
with
typical
ischemic
stroke
,
however
our
observation
that
common
NOTCH
3
variants
may
be
associated
with
risk
of
ischemic
stroke
warrants
further
study
.
Diseases
Validation
Diseases presenting
"first twenty-four exons"
symptom
cadasil
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